The prevalence of IBD increased substantially over the last 50 years. We originally proposed the IBD hygiene hypothesis, which states that living in an exceedingly clean environment affects immune development by altering intestinal flora and fauna, which predisposes to IBD. We also proposed that absence of exposure to intestinal helminths resulting from this hygiene is an important factor contributing to the rise of IBD. Substantial clinical and experimental data suggest that helminths prevent IBD. Helminths regulate host's immunity preventing excessive immune responses. Our central hypothesis is that helminths induce expansion of several distinct regulatory T cell subsets in the gut, with separate regulatory functions that work in concert to limit antigen-specific mucosal effector T cell responses and IBD. This proposal will focus on helminthic control of regulatory-type T cells (e.g. Foxp3+) in the gut because this topic is incompletely addressed, and control of these Tregs appear to be a major mechanism through which helminths protect/treat IBD. There is a critical unmet need to understand the functions of these cells in the gut, independent of parasite mediation. This project has three aims. Aim I. Characterize the regulatory T cell phenotypes induced in the normal gut, following helminth infection, and ascertain if they have distinct functions and can prevent colitis. Aim II. In the state of colitis, study the capacity of distinct helminth-induced, regulatory T cell subsets to reverse ongoing colitis and restrict antigen-driven effector T cell function at the site of colitis. Aim III. Study how regulatory T cells control antigen-specific effector T cell responses in our IBD model Approach: We will use the murine intestinal helminths H. polygyrus (Hp) and T. muris, which are effective at preventing and treating murine IBD. The project employees innovative technology that includes Foxp3+/IL10+ reporter mice and a newly developed Rag/OT2/CD25- transfer model of IBD that permits the study of antigen- specific responses in the gut. We are exploring the novel hypothesis that Hp-induces gut regulatory T cell subtypes which control gut antigen-specific T cell responses and IBD. Our long-term objective is to develop new drugs to treat IBD that can act independent of helminths to trigger these regulatory pathways.